While the incidence of adenocarcinomas of the esophagus (EAC) and of the esophagogastric junction (EGJAC) continue to rise, the prognosis remains poor. Despite the accumulation of data regarding the somatic genetics of EAC and Barrett esophagus (BE), the etiology of genetic predisposition to BE and EAC/EGJAC is still unknown. Preliminary investigations in the literature and our own multi-disciplinary, multi-center group, the Ohio Familial Barrett Esophagus Consortium (OFBEC), have revealed that approximately 20% of BE have familial aggregations which comprise BE, EAC and/or EGJAC, and that the inheritance pattern is most likely autosomal dominant. Further, the PI has a putative susceptibility locus on chromosome 20 with suggestion of linkage to BE/EAC in a single multiplex family. Two small families are consistent with linkage to this putative locus and 2 others are not linked. This proposal will, therefore, test the hypotheses: 1. There exist at least two susceptibility genes predisposing to BE/EAC; and 2. These susceptibility genes that play a role in germline predisposition to familial BE/EAC are tumor suppressor genes which also play some rote in the genesis of sporadic BE and EAC. First, using a 400-marker autosomal genome scan, the PI will seek to confirm the chromosome 20 linkage and will determine what fraction of all affected families are linked to this putative locus. At the same time, the PI will seek the other putative locus (loci) which is linked to FBE/EAC/EGJAC. Second, the PI will use array-based expression analysis to look for genes whose transcripts are over- or under-expressed that reside within the critical interval in chromosome 20 as well as within novel regions defined by genome scan. Together with LOH analysis in these regions, this will supplement virtual physical mapping and candidate gene analysis in searching for the susceptibility genes for familial BE/EAC/EGJAC. If successful, this project promises to yield clues to the genetic etiology (and hence genetic risk) for BE, EAC and EGJAC. This might facilitate molecular diagnostics and early prediction as well as targeted surveillance and prophylaxis.